過敏性腸症候群モデルマウスの結腸過敏に関与するHMGB1の由来細胞の同定とRAGE拮抗薬azeliragonおよび関節炎・腸炎治療薬sulfasalazineを用いた予防的介入

• Published in: 日本薬理学会年会要旨集 p. 3-B-P-015
• Main Authors: 岡村, 悠太, 佐々木, 花菜, 堂本, 莉紗, 豊岡, 尚樹, Eunkyung, Shin, 川畑, 篤史, 坪田, 真帆, 友野, 靖子, 関口, 富美子, 西堀, 正洋, 岡田, 卓哉
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2023
• Subjects: colon; pain; sensory neuron
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.97.0_3-B-P-015

Nuclear HMGB1, once acetylated by histone acetyltransferase, is released following its cytoplasmic translocation, which is negatively regulated by histone deacetylase (HDAC). Given the involvement of HMGB1 and its membrane receptors including a receptor for AGEs (RAGE) in colonic hypersensitivity caused by butyrate able to inhibit HDAC in mice, a model for irritable bowel syndrome (IBS), we aimed at identifying cells that release HMGB1 in response to butyrate and testing whether azeliragon (AZG), a RAGE antagonist, and sulfasalazine (SSZ), an anti-arthritis/anti-colitis medicine, prevent the butyrate-induced colonic hypersensitivity. Repeated intracolonic butyrate administration caused colonic hypersensitivity, which was prevented by an anti-HMGB1-neutralizing antibody, a macrophage (Mφ) depletor, AZG or SSZ. Butyrate treatment increased Mφ count and cytoplasmic HMGB1 distribution in Mφ and enteric glial cells (EGCs) in the colonic mucosa. Butyrate evoked HMGB1 release from Mφ-like RAW264.7 and EGC-like CRL-2690 cells, which was inhibited by SSZ. Our data suggest that the accumulating Mφ as well as EGCs in the colonic mucosa releases HMGB1 in response to butyrate, resulting in colonic hypersensitivity, and that AZG and SSZ prevent the development of colonic hypersensitivity accompanying IBS by inhibiting the HMGB1/RAGE pathway.